Beruflich Dokumente
Kultur Dokumente
INSERM U426, Faculte de Medecine X. Bichat, Universite Paris 07, Paris, France; Nephrology and Renal
Transplant Unit, Hopital Saint Louis, Paris, France; Nephrology and Renal Transplant Unit, Hopital
Europeen George Pompidou, Paris, France; Department of Biostatistics, Hopital Saint Louis, Paris, France;
Nephrology and Renal Transplant, Hopital de Valenciennes, France; Pathology Unit, Hopital Europeen
George Pompidou, Paris, France.
Henoch-Schonlein purpura (HSP) is a leukocytoclastic vasculitis involving small vessels with the deposition of immune
complexes containing IgA. It is characterized by the association of skin, joint, and gastrointestinal manifestations that may
occur in successive episodes (1). In addition to these manifestations, renal involvement is common, and the long-term prognosis depends on its severity.
HSP primarily affects children, and its incidence is approximately 15 cases/100,000 children per yr (2); it is less common
in adults. Although HSP has been extensively studied in children, much less is known about its natural history in adults.
Apart from a recent multicenter Italian study (3,4), data on this
disease in adults are confined to small series with relatively
short follow-up (515). In adults, however, the incidence of
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Evaluation
Clinical and Biologic Data. The characteristics of skin manifestations, gastrointestinal and joint symptoms, and renal involvement
were recorded. Hypertension was defined according to World Health
Organization criteria.
We recorded the levels of aspartate and alanine amino transferases
(ASAT, ALAT), bilirubin, alkaline phosphatase, and -glutamyl
phosphatase for hepatic disorders. Serum IgA levels were recorded
when available.
Renal insufficiency was defined as creatinine clearance (CrCl) 50
ml/min (calculated by Cockroft formula [22]): moderate renal functional impairment as CrCl between 30 and 50 ml/min, and severe renal
failure as CrCl 30 ml/min. Proteinuria was defined as proteinuria
0.1 g/d, and nephrotic syndrome as plasma albumin 30 g/L and
proteinuria 3 g/d. Hematuria was defined as 10 red cells/mm3 in
the urine, and was macroscopic if 1500 red cells/mm3.
Renal Pathology. All renal biopsies were independently examined by two pathologists blind to clinical features. On immunofluorescence, the predominance of mesangial IgA among glomerular Ig
deposits was required. To be adequate, at least ten glomeruli had to be
present. We evaluated semiquantitatively: (1) endocapillary lesions
and their focal or diffuse distribution; (2) extracapillary proliferation,
graded according to the number of glomeruli involved; (3) interstitial
fibrosis (% of the parenchyma involved); (4) interstitial cell infiltration, tubular necrosis, and red cell casts, graded from 0 to 3
depending on the extent of the parenchyma involved; and (5) arteriolar hyalinosis and arteriosclerosis (from 0 to 3). The proportions of
glomeruli involved by crescents, fibrinoid necrosis, and global sclerosis were recorded. All biopsies were then classified according to the
following classification:
1. Mesangiopathic glomerulonephritis. Histologically normal glomeruli by light microscopy or minimal mesangial prominence.
2. Focal and segmental glomerulonephritis. Segmental endo- and
extracapillary proliferation involving less than 50% of the glomeruli. The remaining involved and uninvolved glomeruli were either
normal or exhibited minimal mesangial prominence.
3. Endocapillary proliferative glomerulonephritis, divided into two
subclasses: 3(a), moderate pure endocapillary proliferative lesions;
3(b), severe endocapillary proliferation, possibly with extracapillary proliferation involving less than 50% of the glomeruli.
4. Endocapillary and extracapillary glomerulonephritis. Lesions were
as above, with crescents involving more than 50% of the glomeruli.
5. Fibrotic kidney with global glomerular sclerosis involving more
than 50% of glomeruli.
Outcome. We evaluated the outcome of each patient, as of the
reference date of July 1, 2000. For patients who died, the cause of
death and renal status at death were determined. When patients were
lost to follow-up, their renal status at the last visit was recorded. Renal
outcome was classified as remission (no renal failure, proteinuria, or
hematuria); persistent proteinuria and/or hematuria without renal insufficiency; moderate or severe renal insufficiency as defined above;
and end-stage renal failure (ESRF).
Statistical Analyses
Results were expressed as numbers (percentages) for categorical
variables and as median (1st to 3rd quartiles: Q1 to Q3) or mean (
SD), as indicated, for continuous variables. Comparisons were based
on the 2 test for categorical variables and Wilcoxon or KruskallWallis tests for continuous variables. Survival curves from the day of
renal biopsy were computed using Kaplan-Meier estimate. A Cox
model was fit to evaluate the influence of the following variables on
severe renal failure occurrence: age, CrCl, proteinuria level, hematuria, the pathologic classification, the percentages of crescents, necrotic
glomeruli, sclerotic glomeruli, interstitial fibrosis, and the use of
specific treatments. For model selection, we used stepwise forward
selection. All tests were two-tailed, and P 0.05 was considered
significant. Statistical analyses were performed with SAS 6.12 software (SAS Institute, Cary, NC).
Results
Extrarenal Presentation
The median age at HSP onset was 50 (range, 15 to 86 yr). At
the reference date, the median duration of follow-up was 14.8
(13.1 to 20.8) yr. Male/female ratio was 1.7. In 80 (32%) of our
250 cases, there was a recent history of intercurrent infection,
mostly of the upper respiratory tract.
Most patients (96%) had purpura, always localized to the
lower limbs. Other parts of the body were sometimes involved,
but rarely the face or mucosa (5%). Blisters and hemorrhagic
necrotic skin lesions occurred in 35% of the patients. Relapses
of purpura were observed in 48%. Most of them only relapsed
once, but in rare cases, up to ten times. Arthritis occurred in
61% of the cases, was symmetrical, and the joints most often
involved were the knees or the ankles. Gastrointestinal involvement was observed in 120 cases (48%). The main symptom was colicky abdominal pain. Bleeding occurred in 61
cases of gastrointestinal involvement (51%) and was serious,
requiring transfusion or surgery or leading to death, in 13 cases
(11%). Purpura was the first clinical manifestation in 83% of
the cases, arthritis in 9%, and gastrointestinal involvement in
8%. Renal manifestations preceded clinical symptoms in only
two patients (4 and 5 mo before, respectively).
We frequently observed mild, usually brief, liver disorders,
with evidence of liver cell damage (15%) or cholestasis (87%).
Elevated levels of IgA were found in 118 of the 196 patients
tested (60%). Positive anti-neutrophil cytoplasmic antibody
was found in 4 of the 105 patients tested (3.8%).
Clinical and biologic presentations differed among patients
according to age, as shown in Table 1. More patients aged 30
yr had a recent history of intercurrent infection and arthritis
than older patients. By contrast, in those aged 60 yr, purpura
was much more frequently necrotic, IgA levels were higher,
and CrCl was much lower (this last out of proportion to the
differences expected on the basis of age).
Renal Features
Evidence of renal involvement was detected within a median
period of 2 mo (range, 1 to 4 mo) after onset of the first clinical
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Table 1. Clinical and biologic presentation of Henoch-Scho lein purpura (HSP) according to agea
Parameter
Age 30 yr
(n 54)
Age 30 to 60 yr
(n 111)
Age 60 yr
(n 85)
54.7%
71.7%
16.7%
3 0.2
99 5
28.4%
67.9%
36.4%
4 0.2
90 3
23.5%
48.2%
44.7%
5 0.3
46 3
0.0004
0.005
0.0001
0.0001
0.0001
symptoms. All patients exhibited some evidence of renal abnormality at the time of biopsy. Nineteen patients (36%) had
high BP, but most of them had a past medical history of
hypertension. Of the 250, 169 patients (68%) had normal and
81 (32%) impaired renal function. Renal function impairment
was moderate in 46 cases (18%) and severe in 35 cases (14%).
Proteinuria was generally mild (66% had 3 g/24 h), and 28%
of the patients had nephrotic range proteinuria. Hematuria was
microscopic in 85% and macroscopic in only 25 patients (10%)
(Table 2).
Pathology
The most frequent lesion in renal biopsies was proliferative
endocapillary glomerulonephritis (class 3) (61%). Proliferative
endo- and extracapillary glomerulonephritis (class 4) was only
present in 21 cases (8%). In these cases, the mean percentage
of glomeruli containing extracapillary proliferation was 62
4%. Circumferential crescents involving all glomeruli were
only seen in four biopsies. Fibrinoid necrosis of the glomerular
tuft was present in 48% of biopsies. The mean percent of
glomeruli per biopsy affected by fibrinoid necrosis was below
5% in classes 1, 2, and 3a, 14 2% in class 3b, and 19 5%
in class 4. Inflammatory infiltrates and interstitial fibrosis were
Renal function
normal
moderately impaired
severely impaired
Proteinuria
0.1 g/24 h
0.1 to 1 g/24 h
1 to 3 g/24 h
3 g/24 h
nephrotic
Hematuria
no hematuria
microscopic
macroscopic
Hypertension
67.6
18.4
14.0
4
25.6
38.8
31.6
27.9
5.6
84.6
9.8
36
Outcome
The patient survival curve is shown in Figure 1A. Sixty-four
patients (26%) died. Median survival time was 15 yr (range, 13
to 21). The mean age at death was 67.3 1.5 yr. The most
frequent cause of death was neoplasia in 17 patients (27% of
deaths), involving lung in nine patients and upper respiratory
and digestive tracts in five. Eleven of the seventeen patients
dying of cancer never received any immunosuppressive treatment, four had been treated by corticosteroids alone, and two
by corticosteroids associated with cyclophosphamide (P
0.05). They thus did not differ significantly from the remaining
patients as regards treatment. The mean delay between renal
biopsy and death was 42 7 mo (range, 5 to 118 mo).
The second cause of death was infection (16%). Eight of the
twelve lethal infections were attributable to immunosuppressive treatment. The mean delay between renal biopsy and death
there was 11 3 mo (range, 2 to 41 mo). Death was secondary
to HSP evolution in seven patients (11%), due particularly to
severe digestive involvement. Cardiovascular diseases were
responsible for the death of six patients (9%). The ratio of
cardiac to cancer deaths in our patients was thus reversed
compared with that in the general population.
The renal survival curve is shown in Figure 1B. Twentyseven patients (11%) developed ESRF. Those who went into
ESRF tended to do so rather rapidly, 13 (48%) of 27 by 3 yr,
and all but 2 of 27 patients by 10 yr. Twenty-five patients were
dialyzed, and 12 were renal transplant recipients. None of these
recipients lost their graft because of a relapse of HSP. Thirty-
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two patients (13%) had severe renal failure, and 35 (14%) had
moderate renal insufficiency. In all, 94 (38%) of the 250
patients exhibited significant renal insufficiency.
At the end of the follow-up, only 20% of the patients were
in clinical remission. Among the other patients, 50% had
microscopic hematuria (isolated in 30 cases), 47% had minimal
or moderate proteinuria, and 8% had nephrotic-range proteinuria. Thirty-eight patients (15%) were lost to follow-up after a
median of 1.8 yr (range, 0.9 to 4.1). Seven of them were in
clinical remission at the time of their last examination.
Univariate Analyses. Table 3 shows the clinical and histologic data for patients at the time of renal biopsy categorized
according to their renal outcome. Prognostic factors for severe
renal impairment are shown in Table 4. Age over 50 yr at onset
was a strong predictor of severe renal failure (relative risk [RR]
2.53; P 0.0012); 66% of the patients with severe renal
failure at their last visit were older than 50 yr at initial biopsy,
and similarly, the mean age of patients with severe renal failure
at the end of follow-up was significantly higher than that of
patients with normal renal function (65 versus 43.5 yr). Clinical presentation, including purpura, arthritis, and abdominal
involvement, was not associated with a significant difference
in renal function at the end of the follow-up. The presence of
renal failure at onset was the strongest predictive factor of renal
failure at the end of follow-up (RR 5.86; P 0.0001); thus
69% of the patients with severe renal failure at presentation had
severe renal failure at the end of follow-up. Proteinuria 1 g/L
(RR 2.13; P 0.0012) and the presence of macroscopic
hematuria (RR 2.13; P 0.038) at biopsy correlated the
CrCl at the end of follow-up, but the presence of nephroticlevel proteinuria was not predictive of a poor outcome.
As shown in Table 3, the pathologic process was more
predictive of the renal prognosis than the clinical presentation.
The glomerular classification was predictive of the renal outcome (P 0.0002). Of the 74 patients with class 1 and class
2 glomerulonephritis, 61 (82%) exhibited normal renal function at the final consultation, and only 11 (15%) exhibited
severe renal failure. In contrast, of the 90 patients with severe
endocapillary proliferative glomerulonephritis (biopsy classes
3b and 4), 47 (52%) exhibited normal renal function at the final
Therapy
Therapy was administered to 140 patients (56%). Steroids
alone were given to 93 (37%), associated with cyclophosphamide to 47 (19%), and cyclophosphamide alone to only one
patient. Levels of proteinuria (1.7 0.2 g/24 h versus 3.7
0.3; P 0.0001) and creatinine (125.4 9.3 mol/L versus
154.7 12.6; P 0.05) were significantly higher in the
treated group of patients. Treatments differed according to the
glomerular classification. The worse the lesion, the greater the
probability that the patient would be treated and that the
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Table 3. Renal outcome in relation to clinical, biologic, and histologic data at the time of renal biopsya
Outcomes Observed during Long-Term Follow-Up
Variable at Biopsy
Age (yr)
CrCl (ml/min)
Hematuria (%)
absence (n 18)
microscopic (n 208)
macroscopic (n 24)
Proteinuria (%)
1 g/24 h (n 81)
1 to 3 g/24 h (n 85)
3 g/24 h (n 84)
Biopsy classification (%)b
class 1 (n 28)
class 2 (n 46)
class 3a (n 82)
class 3b (n 69)
class 4 (n 21)
class 5 (n 3)
Glomerular necrosis (%)
Glomerular sclerosis (%)
Interstitial fibrosis (%)
a
b
Normal Renal
Function n 160
Moderate Renal
Failure n 31
Severe Renal
Failure n 59
64 (59 to 75)
39.6 (28.3 to 51.7)
65 (35 to 73)
34.3 (18.7 to 57.9)
15 (9.4)
132 (82.5)
13 (8.1)
2 (6.5)
27 (87.1)
2 (6.5)
1 (1.7)
49 (83.0)
9 (15.3)
0.2
60 (37.5)
49 (30.6)
51 (31.9)
12 (38.7)
8 (25.8)
11 (35.5)
9 (15.3)
28 (47.5)
22 (37.3)
0.02
26 (16.4)
35 (22.0)
51 (32.1)
36 (22.6)
11 (6.9)
0
0 (0 to 9)
3 (0 to 11)
0 (0 to 10)
1 (3.2)
1 (3.2)
15 (48.4)
11 (35.5)
3 (9.7)
0
0 (0 to 15)
9 (0 to 20)
10 (0 to 20)
1 (1.7)
10 (16.9)
16 (27.1)
22 (37.3)
7 (11.9)
3 (5.1)
6 (0 to 17)
18 (1 to 42)
20 (10 to 30)
0.001
0.001
0.0002
0.3
0.001
0.001
Data are n (%) or median (quartiles). See Materials and Methods (Renal Pathology) for biopsy classification.
n 249; one biopsy was excluded (only one glomerulus).
Discussion
The goal of this study was to define the long-term prognosis
and risk factors for severe renal failure in adults with HSP
nephritis. In contrast to previous outcome studies of comparable adult populations, multivariate analyses could be performed here because of the larger number of patients and the
length of follow-up. We demonstrated that the clinical presentation of HSP is more severe in older adults and that the renal
prognosis for HSP nephritis is poor compared with what is
observed in series in children. It should be stressed that we
studied a group of selected patients whose HSP-exhibited renal
involvement severe enough to warrant renal biopsy.
Our study extends the findings of previous studies (4 14,15)
conducted in smaller series. The patients in our population
were roughly comparable to those previously described by
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Relative Risk
Age 50 yr
Creatinine 120 mol/L
Proteinuria 1 g/24 h
Macroscopic hematuria
Corticosteroids alone
CS Cy
Biopsy classification
class 1
class 2
class 3a
class 3b
class 4
class 5
Presence of crescents
Glomerular necrosis
10%
Glomerular sclerosis
10%
Interstitial fibrosis 10%
2.53
5.86
2.13
2.13
1.98
1.5
1
9.02
6.52
11.7
11.99
64.48
0.78
1.95
95% CI
1.44 to 4.45
0.0012
3.30 to 10.44 0.0001
1.6 to 6.64
0.0012
1.04 to 4.35
0.038
1.14 to 3.44
0.015
0.82 to 2.74
0.19
1
1.14 to 71.29
0.86 to 49.59
1.57 to 87.33
1.44 to 99.75
6.61 to 629
0.28 to 2.16
1.15 to 3.31
0.037
0.07
0.016
0.022
0.0003
0.64
0.013
2.94
a
For biopsy classification, see Materials and Methods (Renal
Pathology). CS, corticosteroids; CY, cyclophosphamide.
Relative Risk
95% CI
4.27
2.98
1.83
2.12
1.053 to 4.54
0.02
3.83
1.036 to 1.78
0.0008
others, but they were older on average, and more of them were
hypertensive. Note, however, that the World Health Organization has recently lowered the measures that define hypertension
(23).
We show here that the presentation of HSP differs significantly with age, as older patients exhibited much more severe
renal and extrarenal manifestations than younger patients.
Coppo et al. (3) has shown that children differ from adults by
more frequent joint manifestations, and that this difference
persists in adulthood, with decreasing joint manifestations as
patients age, a finding that our study confirms and extends
(Table 1). All the studies of children (24 26) show that cutaneous necrosis is uncommon and affects fewer than 5% of
cases. In our adult patients, by contrast, necrotic purpura was
much more common and became increasingly so with age.
Pathologically, we found that 8% of patients had endocap-
Acknowledgments
We are grateful to the following pathologists, who provided listings
of the HSP nephropathy patients and slides of their renal biopsy:
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